Persistent viral infections are a major health problem worldwide. The inability of the immune system to clear infection characterizes life-long persistence by human immunodeficiency virus (HIV-1), Epstein- Barr virus (EBV), Kaposi's sarcoma virus (KSHV), cytomegalovirus (CMV) and hepatitis C virus (HCV). Among them, the 3-herpesviruses are very successful pathogens. EBV infects 95% of the human population. KSHV seroprevalence exceeds 60% in endemic African regions. Due to their association with a large number of diseases a vaccine for 3-herpesviruses is a health priority. Nevertheless, vaccination against persistent viruses in general, and 3-herpesviruses in particular, has proven a challenge. Infection of mice with murine gamma-herpesvirus 68 (MHV-68) provides an invaluable animal model to characterize immune responses in a natural host that may be used to develop vaccines against 3-herpesvirues. In the current proposal, we will identify the immune correlates of protection induced by a novel vaccination strategy that ameliorate acute infection and prevent latency in mice after MHV-68 challenge. Our preliminary data show that after DCS11 vaccination there is a reduction in virus load by a 50,000-fold during acute infection and that viral latency cannot be detected. In Aim 1, we will determine the functional characteristics of the immune response to DCS11 vaccination. In Aim 2, we will identify the mechanism(s) of vaccine protection by analyzing the recall response to a virus challenge in DCS11-vaccinated mice. The information generated by these studies will be critical for our understanding of how vaccines against 3-herpesviruses can elicit protection, and it will likely aid in the development of immune therapies against persistent viral infections. PUBLIC HEALTH RELEVANCE: Persistent viral infections are a major health problem worldwide. The goal of the present application is to determine the immune correlates of protection induced by our novel vaccination strategy that ameliorate acute infection and prevent latency in mice after murine 3-herpesvirus challenge. The information generated by these studies will be critical for our understanding of how vaccines against 3-herpesviruses can elicit protection, and it will likely aid in the development of immune therapies against persistent viral infections.